Thiol compounds exist in many chemical and biochemical systems, and in many cases are undesirable or harmful compounds requiring selective removal or chemical conversion from the system. The thiol group SH (otherwise known as the mercaptan group or the sulfhydryl group) often confers malodorous properties on compounds containing it. Minerals such as mineral fuel deposits (oil, natural gas and coal, for example) are often contaminated with malodorous thiol compounds. Gaseous effluents from the extraction and refining of crude oil, gasification of coal and mining of natural gas are often contaminated with thiols, and require removal of thiols therefrom to meet environmental standards.
The manufacture of certain pharmaceutical products, for example cimetidine, ranitidine and nizatidine, involves the use of sulfur-containing reagents and the production of methyl mercaptan by-products. The current method of disposal of these products is by incineration, which leads to the production of sulfuric acid, discharged as a component of "acid rain". An improved method of trapping thiols in this context is also required.
Thiol trapping agents can be used in diagnostic processes to trap organic mercaptans. Also, they can be used as diagnostic reagents, for example, in the detection of sulfhydryl groups of proteins.
Of particular interest in connection with the present invention is the trapping of biochemical thiol compounds such as enzymes. Many enzymes contain active thiol groups, derived from their cysteine residues. Selective inhibition of the activity of such enzymes, reversibly or irreversibly, by reaction to modify their thiol groups, in a biological system, may thus form the basis of therapeutic treatment. Examples of such enzymes are Cathepsin B, Papain, H.sup.+ /K.sup.+ -ATPase, Interleukin .beta.-1 Converting Enzyme, protein disulfide isomerase (HIV).
Cathepsin B and L have been implicated in a number of diseases, including progressive cartilage and bone degradation associated with arthritis. Inhibitors of these cathepsins have caused reduced inflammation and joint destruction in animal models of arthritis C. The calcium associated proteases calpain I and II have been associated with Alzheimer's disease.
Interleukin beta converting enzyme (M. Mullican et al., Bioorganic & Medicinal Chem. Lett., 1994, 2359) is a key target for drug discovery because of its key role in the release of the inflammatory protein, interleukin-1 b eta. Excessive levels of interleukin-1 beta are implicated in a wide variety of diseases including rheumatoid arthritis, psoriasis, inflammatory bowel disease, and insulin-dependent diabetes. Like thiol protease, its mechanism of action involves a cysteine resides at the active site.
Proposed reversible inhibitors of these enzymes include peptido aldehydes, nitrites, .alpha.-ketocarbonyl compounds. Proposed irreversible inhibitors include peptido halomethyl ketones, diazomethylketones, acyloxymethyl ketones, ketomethylsulfonium salts, epoxides and vinyl sulfones. Although these compounds are known to be thiol protease inhibitors, none of the structural types have found serious utilities as drug candidates.
The enzyme proton pump gastric H.sup.s+ /K.sup.+ -ATPase, also known as the proton pump, has been implicated in the development of peptic ulcers in mammals. This enzyme also contains active thiol groups, derived from their cysteine residues. The inhibition of this enzyme is one of the primary bases of treatment of peptic ulcer in humans. Thiol trapping agents can be used to inhibit the enzyme H.sup.+ /K.sup.+ -ATPase. An example of such compound is omeprazole.